N-Acetyl-L-cysteine (NAC) is approved in United States a mucolytic agent for the treatment of chronic bronchopulmonary disease (chronic emphysema, emphysema with bronchitis, chronic asthmatic bronchitis, tuberculosis, bronchiectasis and primary amyloidosis of the lung) and as an antidote to prevent or lessen hepatic injury following an acetaminophen overdose. D-Penicillamine is also approved in United States for the treatment of Wilson's disease and cystinuria. Both drugs have been proposed for use in treating a wide range of immunological, autoimmune, inflammatory, and/or neurological diseases and conditions.
NAC has been proposed for use in treating interstitial lung disease (Grandjean et al., Clin Ther 2000, 22 (2), 209-21; and Stey et al., Eur. Respir. J. 2000, 16 (2), 253-62); kidney disease induced by radio-contrasting agent (Tepel et al., N. Engl. J. Med. 2000, 343 (3), 180-4); liver disease such as non-alcoholic steatohepatitis (Khoshbaten et al., Hepatitis Montly 2010, 10 (1), 12-16); and psychiatric disorders such as schizophrenia, bipolar disorder, trichotillomania, skin picking, autism, and obsessive-compulsive disorder (Dean et al., Journal of Psychiatry & Neuroscience: JPN 1982, 36 (2), 78-86; Berk et al., Trends Pharmacol. Sci. 2013, 34 (3), 167-77; and Bavarsad et al., Brain and Behavior 2014, 4 (2), 108-22).
D-Penicillamine has been proposed for use in treating scleroderma (Steen et al., Annals of internal medicine 1982, 97 (5), 652-659) and rheumatoid arthritis (Camp, et al., Proceedings of the Royal Society of Medicine 1977, 70 (2), 67-69).
The mechanisms of action of NAC and D-penicillamine for the approved and proposed treatments probably involve a number of pathways. N-acetyl-L-cysteine acts as a prodrug to L-cysteine, which acts as a precursor to the important biological antioxidant glutathione. D-penicillamine possesses a reactive thiol group, which can bind to and help eliminate heavy metal ions such copper and lead from the body.


However, both NAC and D-penicillamine exhibit poor oral absorption characteristics. NAC has an oral bioavailability of only 4-10% (Olsson et al., Eur J Clin Pharmacol. 1988, 34 (1), 77-82) while D-penicillamine showed a high degree of interpatient oral variability (Merck & Co., Inc.). Both compounds can undergo oxidation in the intestine to form disulfides.